Lyme disease is a multisystem illness, transmitted by ticks of the Ixodes ricinus complex. The spirochaete Borrelia burgdorferi sensu lato is the aetiologic agent of Lyme disease, which is now the most common arthropodborne disease in the United States, and is endemic in Central Europe (1). Although curable by antibiotic therapy in its early stages, if Lyme disease is allowed to progress, cardiac, neurological and joint abnormalities can arise. Investigations into the development of a human vaccine for Lyme disease are under way. The outer surface lipoprotein OspA of Borrelia burgdorferi is the current major candidate molecule for development of such a vaccine. Recombinant OspA lipoprotein (rOspA) is known to elicit a protective immune response in mice against challenge by infectious B. burgdorferi (2,3). OspA is currently undergoing human field trials as a subcutaneously administered vaccine in the United States (4).
Above-cited application Ser. No. 08/373,455 and PCT/US92/08697 relate to rOspA vaccines, especially lipidated rOspA, and methods for expressing DNA encoding OspA or fragments thereof. Above-cited application Ser. No. 08/320,416 and WO 90/04411 relate to DNA encoding OspA, the amino acid sequence of OspA, synthetic OspA, compositions containing OspA or synthetic OspA, and methods of using such compositions. And, the other above-cited applications relate to DNA encoding other Borrelia antigens or other Osps, or to DNA encoding useful fragments of OspA or of other Osps or of other Borrelia antigens, amino acid sequences thereof, compositions containing such fragments or other Osps, and methods for using such compositions; and, such DNA can be used in the methods of Ser. No. 08/373,455 or PCT/US92/08697 to produce OspA, other Borrelia antigens or Osps, or fragments thereof, for use in this invention.
Alternative vaccination strategies are desirable as such provide alternative routes to administration, thereby allowing administration to humans who may be sensitive to injections, e.g., young children or infants, or to other hosts with whom there is difficulty giving injections, e.g., wild animals, and even domestic animals.
OspA administered orally in an Escherichia coli was capable of stimulating a mucosal immune response that protected mice against challenge with infectious B. burgdorferi (5). More recently, Dunne et al. reported oral immunization of mice with an attenuated strain of Salmonella typhimurium expressing OspA, which appeared to protect 80% of the mice from challenge by infectious B. burgdorferi (6). Mucosal immunity was also demonstrated following intra-nasal administration of recombinant BCG expressing OspA (7). However, rOspA in E. coli, Salmonella expressing OspA, and, BCG expressing OspA, are not viable products for usefully administering rOspA to humans or animals—domestic or wild—as E. coli, Salmonella and BCG are not safe or approved for administration to humans or animals (and even if attenuated, there is nonetheless a chance of reversion); and, one cannot be certain if any immunological response in these prior publications was not an effect of an adjuvanting or immunological stimulating effect of E. coli, Salmonella or BCG (note, for instance, how LPS is known to have an adjuvanting effect).
Thus, heretofore the art has not taught or suggested mucosal, preferably oral, administration to a mammalian host—domesticated or wild animal or human—susceptible to Lyme disease, of Borrelia antigen or immunological fragment thereof, e.g., OspA, preferably rOspA, more preferably lipidated OspA or rOspA, preferably substantially free of other bacterial proteins and substantially free of lipopolysaccharide (LPS), in a suitable carrier or diluent in an amount sufficient to induce an immunological response preferably a protective immunological response, in the host, preferably without any necessity of using any immunogenicity-enhancing adjuvant; or compositions therefor; and, the protection by such administration herein demonstrated has not been heretofore taught or suggested. Further, heretofore the advantages of such oral administration, e.g., ease of administration to domestic animals and young children or infants by merely droppering into the mouth, ease of administration to wild animals by dropping bait containing the OspA or rOspA, has not been taught or suggested.